Herbal supplements are often used concomitantly with conventional medications resulting in considerable potential for herb-drug interactions. These interactions, which are generally through interfering with pharmacokinetic and/or pharmacodynamic pathways, may result in beneficial effects or more often adverse reactions such as toxicity or treatment failure and may be influenced by multiple environmental and/or genetic factors. The pharmacogenetic approach may help to identify some interactions which may be more pronounced or only occur in specific groups of subjects although the complex nature of the herbal medicines may limit the discovery of such an interaction. Preclinical studies such as gene expression profiling in rodent liver may help to define metabolic pathways influenced by herbal medicines and facilitate more accurate targeting of human in vivo studies. This review discusses the mechanisms of herb-drugs interaction and the potential influence of genetic variation on herb-drug interactions based on available clinical evidence.